{"paper_id":"a1f1cf8b-6f95-47a9-bda1-5a755020da06","body_text":"In women of the reproductive age, uterine fibroids\n(leiomyoma) are monoclonal is a benign and most\ncommon gynecological tumor that depends on hormonal changes ( 1 - 5 ). These tumors affect 25-80% of\nreproductive age women depending on their demographic characteristic [race, age, and body mass index\n(BMI)], past medical history [hypertension (HTN),\ninfertility, and premenopausal period], nutritional\nhabits (use of food additive or soy bean milk) and\nfamily history ( 6 - 9 ).\nIt has been reported that some intrinsic abnormalities\nduring the menstrual period including abnormal myometrial receptors for estrogen and hormonal changes or altered responses to ischemic injury, may be accountable\nfor the start of (epi) genetic changes found in uterine myomas ( 10 ,  11 ).\nMost uterine fibroids are asymptomatic, but they can\ncause symptoms, according to their size and location, like\nabnormal or heavy menstrual bleeding, iron deficiency\nanemia, bloating, constipation, urinary symptoms, pelvic\npain, problems in intercourse, or pregnancy complications like recurrent miscarriage, premature labor and infertility ( 5 ,  12 - 16 ).\nSymptomatic tumors are mainly treated by surgery.\nIn addition to high direct costs of fibroma surgery treatments, these treatments are not suitable for women\nwho wish to maintain fertility. However, nonsurgical\ntreatments are approved just for short-term treatment\nand have their own disadvantages ( 5 ,  17 ). On the other hand, some therapeutic agents like gonadotropin\nhormone-releasing hormone (GnRH) analogue, oral\nGnRH antagonist (Elagolix), selective progesterone receptor modulators (SPRM), vitamin D (vitD) and green\ntea extracts are candidates to blunt the fibroid growth\n( 18 ,  19 ).\nOf medical therapeutic agents, vitD is a safe, inexpensive and available treatment without\nmajor side effects in therapeutic dose, which is assumed theoretically as an antitumor agent\n( 20 ). It modulates gene (like cell growth and division genes and encoding estrogen and\nprogesterone receptors genes) expression via vitD receptor and can result in regulation of\ncellular proliferation and cellular differentiation, stimulation of apoptosis that finally\nresults in inhibition of malignant transformation and prevention of tumor cells\nproliferation ( 21 ,  22 ). Exposure to 1α, 1,25(OH) 2  D 3  inhibits the\ngrowth of melanoma, and lung, colon, prostate and breast cancer ( 23 - 27 ). So, vitD can be\nassumed as a preventive tool for high-risk group of patients that are susceptible to uterine\nfibroma ( 28 ).\nSince, there is a high prevalence of vitD deficiency\nin Iran, there are interesting articles about the theoretical role of vitD in growth inhibition of uterine\nfibroid and the present data are inadequate to show\nthe role of vitD as a medical therapy for the treatment of uterine fibroids, there is a need for a clinical trial that can assess inhibitory effects of vitD on\nthe uterine fibroid size. Therefore, we conducted a\nrandomized blinded clinical trial for evaluating the\neffects of vitD on the leiomyoma mean diameter in\nwomen with at least one uterine fibroid>10 mm referred to gynecology clinic in Tehran University of\nMedical Sciences’ Hospital.\n\nThis randomized blinded clinical trial was conducted\nbetween August 2017 and September 2018 in a tertiary\nuniversity-based hospital.\nAll reproductive age women who referred to gynecologic clinic and had at least one uterine fibroid>10\nmm in transvaginal ultrasound, were evaluated using\na blood sample for vitD levels. According to the Endocrine Society Practice Guideline on vitD status, deficiency was defined as vitD<20 ng/ml, insufficiency\nas 21-29 ng/ml, and sufficiency as at least 30 ng/ml\n( 29 ).\nAll the patients with uterine fibroid and insufficient levels of vitD (21-29 ng/ml) were\nincluded in the present study. Due to ethical concerns, patients with deficient levels of\nvitD (<20 ng/ml) were excluded from the study and received vitD as treatment. Other\nexclusion criteria were refusing follow-up visit or being candidate for hysterectomy or\nmyomectomy due to related symptoms of uterine fibroid like bleeding, pain, pregnancy,\nmenopause, use of oral contraceptive during the last 3 months, consuming vitD supplements\nduring the last 3 months, having BMI of <18 or >30 kg/m 2  ( 30 ) and\nmalignancy\nTwo-hundred and forty women with uterine fibroid\nwere referred to the clinic. Of them, 20 patients had\nsufficient levels of vitD, and seven patients underwent\nsurgery in the control group and eight patients in the\nintervention group and one woman with unwanted\npregnancy was excluded from the control group during the study. To tally 204 women, 102 in each group,\ncompleted the study protocol and data was analyzed\n(according to intention to treat analysis) ( Fig.1 ).\nThe vitD level was measured by a Kit (Narvanteb\nCompany Kit, Iran) based on a chemiluminescence\ntechnology. Each patient had two blood samples, one\nin the initiation of the study and one after 8 weeks of\nobservation or treatment with vitD in the same laboratory following the same method.\nAccording to the sample size formula (α=0.05,\nβ=90%, r=-0.31), we needed 212 patients for this study\n(106 patients for each groups) ( 30 ). Randomization of\nthe patients was done based on block randomization\nby a computer program (Random Allocation Software)\nthat was performed by a secretory that was blinded to\nthe study group.\nThe uterine fibroid size was measured by a radiologist who was experienced in gynecologic ultrasound\nin the initiation of study and after 8 weeks of treatment with vitD supplement for both study groups.\nThe radiologist was blinded to the grouping. Uterine\nfibroid was defined as well-defined, hypoechoic, heterogenous mass. Regarding the anatomical site in the\nuterus, patients divided as subserosal if the development was in the outer portion of uterus, intramural if\nthe leiomyoma localized in the myometrium, and submucosal if the development was in to uterine cavity.\nThe leiomyoma was measured by three perpendicular\ndiameter and the mean of them was calculated. The\nscans were performed by a 5.5-MHZ probe of Voluson\n730 GE Healthcare, Milwaukee, WI.\nThe intervention group with insufficient levels of\nvitD, received vitD 50000 IU (D-Vigel 50000, DaanaPharma Company, Iran) orally once per a week for 8\nweeks and then a blood sample for vitD levels measurement was collected and the second transvaginal ultrasound was performed (1 to 2 weeks after the last dose\nof vitD). The control group with insufficient levels of\nvitD was observed for 8 weeks without vitD supplementation and 1 to 2 weeks after that the second blood\nsample was collected and transvaginal ultrasound was\nperformed, then they received vitD supplement to reach\nsufficient vitD concentration.\nFinally, variations in the mean diameter of uterine\nfibroid and vitD levels were measured and compared\nbetween thetwogroup as the primary outcomes.\nConsort flow diagram of study.\nAll the statistical analyses were performed using SPSS\nversion 24.0 (IBM, New York, USA). Quantitative data\nare expressed as mean ± standard deviation and categorical data are expressed as frequency and percentage. The\nKolmogorov-Smirnov test was used to evaluate the distribution of the data. Independent samples, one-sample\nt test and Crosstabs were used in assessing the variable\nrelationship. P<0.05 was considered significant.\nThe study was approved by the local Ethical Committee\n(IR.TUMS.VCR.REC.1396.2701) and the trial was registered as IRCT201703122576N15. All the patients signed\nthe informed consent before being enrolled in to the study\ngroups.\n\nTotally, 204 women, 102 in each group, completed the study protocol, and data were\nanalyzed. The mean age and BMI in the control and intervention group were 37.21 and 34.89\nyears and 26.71 and 25.63 kg/m 2  respectively. About 6.86% of women had a history\nof infertility in the intervention group versus 5.88% in the control group. The group were\nnot statistically different in terms of age, BMI and history of infertility ( Table 1 ).\nThe mean vitD levels in the control and intervention\ngroup was 23.62 and 23.20 ng/ml, respectively which\nwas not statistically different. At the end of the study, the\nmean vitD levels in the control and intervention group\nwas 22.72 and 28.56 ng/ml, respectively.\nThe mean uterine fibroids diameter in the control\ngroup before and after the study was 41.98 ± 5.25 and\n47.813 ± 3.42 mm, respectively. The mean uterine\nfibroid size increased for 14.5% in control group.\nMean vitD levels before and after the study were 23.6\nand 22.7 ng/ml, respectively in the control group. It\nshowed 0.9 unit or 4% decrement; the levels were\nassumed stable, if the laboratory error was considered\n( Fig.2 ).\nDemographic data of women in the two groups\nData are presented as mean ± SD or n (%). BMI; Body mass index.\nRegarding the site of uterine fibroids in the control\ngroup, 43.14% of them were subserosal, 44.12%\nintramural and 12.75% submucosal. In the intervention\ngroup, 49.02% were subserosal, 42.16% intramural, and\n8.82% submucosal uterine fibroid.\nDiagram of variations in the mean diameter of uterine fibroid\nin the two groups.\nThe most common type of uterine fibroids in the control\ngroup was intramural followed by subserosal, versus the\nintervention group in which, the subserosal was the most\ncommon type followed by intramural. The submucosal\nleiomyoma had the lowest incidence in both groups.\nThe mean uterine fibroid size in the intervention group\nbefore and after the study was 43.09 ± 14.36 and 42.61\n±15.53 mm, respectively. The size decreased to 0.48 mm.\nMean vitD levels before and after intervention qwew23.2\nand 28.5 ng/ml, respectively. It showed 5.36 unit or 24%\nincrease in vitD levels ( Fig.3 ).\nThe change in the size of the uterine fibroid between the\nintervention and control group had a significant difference,\nthe mean changes in size was 5.83 mm in the control group\ncompare to - 0.48 mm in the intervention group (P=0.001).\nThe control group had increases in size versus a slight\ndecrease in the intervention group ( Table 2 ).\nDiagram shows vitamin D levels in both group, before and after\nthe study.\nComparison of uterine fibroid size and vitD level changes in\nthe two groups after the intervention\nData are presented as mean ± SD or %.\nThe mean uterine fibroid size changes in the control\ngroup regarding the type of uterine fibroid was 5.15,7.33,\nand 2.92 mm for subserosal, intramural, and submucosal,\nrespectively. Maximum change in mean leiomyoma\ndiameter was found for intramural followed by subserosal.\nThe mean uterine fibroid size changes in the intervention\ngroup was 0.3 mm decrease for intramural and subserosal\nbut for submucosal 2.33 mm decrease in size occurred\nafter the intervention.\nFor evaluating the error of measurement of uterine\nfibroid diameter, another analysis was done and it showed\nthat the mean change was 4.54 and -0.17 mm for the\ncontrol and intervention group, respectively (P=0.001).\n\nThis trial showed that vitD given to at a therapeutic\ndose vitD insufficient women, can inhibit the leiomyoma\ngrowth which was detectable by ultrasound; however,\nwomen in the control group (who did not receive vitD\ntreatment) had some growth in leiomyoma size.\nThere are some articles about the role of vitD as antitumoral agent ( 7 ,  9 ,  17 ,  19 ,  28 ). The\nreceptor of vitD is a nuclear receptor which is activated by 1, 25(OH) 2 \nD 3  , resulting in modulation of the transcription rate of target gene (like\ncell growth and division genes and estrogen and progesterone receptors encoding genes) ( 31 ).\nThese functions are the orgin of anti-tumor effects of 1,25(OH) 2  D 3  on\nuterine fibroid.\nAccumulating evidence suggests that the metabolic\npathways of vitD may play a key role in the developing of several gynecological diseases. Indeed, the vitD\nreceptor (VDR)-mediated signaling pathways and vitD\nlevels seem to (deeply) affect the risk of polycystic ovary\nsyndrome (PCOS), endometriosis, infertility, ovarian and\neven breast cancer, and affect a woman’s response to\nmenopausal status ( 32 - 35 ).\nAlso another study evaluated vitD concentration and\nuterine fibroid in premenopausal women by ultrasound\n( 36 ). About 90% of black women and 50% of white\nwomen had insufficient vitD levels. These women had\n62% chance of uterine fibroid in comparison with women\nwho had sufficient vitD concentrations.The study was\nshowed that sufficient levels of vitD are associated with\ndecreased risk of liomyoma. VitD concentration was\nchecked from stored plasma of patients and 620 blacks\nand 416 whites were evaluated. Their samples were\nrandomly chosen from National Institue of Environmental\nHealth Sciences Uterine Fibroid Study during 1996-\n1999. Women were asked regarding sun exposure by a\nquestionaire that evaluted sun exposure>1 hour/day\nAnother cross-sectional study ( 37 ) showed that 52\nwomen with uterine fibroid diagnosed by magnetic\nresonance imaging (MRI) or ultrasound had vitD\nlevel<30 ng/ml. The study showed that 85% of women\nwith documented uterine fibroid were vitD deficient and\nthat confirmed our study results.\nAnother prospective cross-sectional study in Turkish\npremenopausal women showed that traditional costume,\nbeing a house wife and low eduction are risk factor for vitD\ndeficiency. Also, the study showed that vitD defficiency\nin women with leiomyoma was more prevalent versus in\nwomen without leiomyoma ( 38 ).\nMoreover, a study by Mitro and Zota ( 39 ) in 3590\nwomen with uterine leiomyomata, in the National Health\nand Nutrition Examination Survey indicated that there was\nno relationship between vitD and odds of uterine fibroids.\nAlthough, subgroup analysis performed on the same\ndata showed that insufficient serum vitD was associated\nwith significantly higher odds of uterine fibroids in white\nwomen but not in black patients.\nIn vivo  vitD production is affected by sun exposure, geographical\nlocations, latitude, season, weather condition, clothing and use of sunscreens have an\nimportant effect on vitD level. Indoor activity and dark skin are risk factor for black\nhouse-wife women for having fibroma ( 28 ,  40 ).\nThe strengths of our study were the design as a randomized\nclinical trial and accurate inclusion and exclusion criteria.\nThe limitation of the present study is the short follow-up\nperiod (i.e.8 weeks). We recommend a clinical trial with\nlonger period of follow-up (i.e. 12 months) for further\nmeasurement of leiomyoma size. Another limitation was\nthat due to ethical considerations, we could not include\nwomen with vitD<20 ng/ml in the study and compare the\neffect of treatment on these women with the control group,\nand the reluctance of patients to participate in the study\nwere another limitations of this study\n\nOur results showed that vitD supplementation prevents\nfibroid growth. It seems that vitD supplement is a simple,\nsafe and inexpensive modality for leiomyoma growth\nprevention.","source_license":"CC-BY-4.0","license_restricted":false}